Crystalline dibenzothiazepine derivative and its use as an antipsychotic agent

ABSTRACT

Crystalline 11-(4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinyl)-dibenzo[b,f] [1,4]thiazepine (I) may be prepared by crystallising 11-(4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinyl)-dibenzo[b,f] [1,4]thiazepine from a non-aromatic solvent such as ethyl acetate, isobutyl acetate, methyl iso-butylketone or methyl tert-butyl ether, preferably in the absence of water. The crystalline material produced may be converted into a pharmaceutically acceptable salt such as a fumarate. The crystalline 11-(4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinyl)-dibenzo [b,f] [1,4]thiazepine may be used to treat psychoses.

[0001] The present invention relates to a process for the preparation ofthiazepine derivatives and, in particular. to the preparation of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineand salts thereof.

[0002] The compound,11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine(Formula I)

[0003] exhibits useful antidopaminergic activity and may be used. forexample as an antipsychotic agent with a substantial reduction in thepotential to cause side effects such as acute dystonia, acutedyskinesia. pseudo-Parkinsonism and tardive dyskinesia.

[0004] The compound of formula I is described in granted European PatentEP 240,228. This patent describes the properties of the compound offormula I and its synthesis fromdibenzo[b,f][1,4]thiazepine-11(10-H)-one. In this synthetic route it isnecessary to prepare and purify the compound2-(2-hydroxyethoxy)ethyl-1-piperazine (HEEP).

[0005] Granted European Patent EP 282,236 describes an improved processfor the preparation of the compound of formula I which obviates the needto prepare and purify the compound2-(2-hydroxyethoxy)ethyl)-1-piperazine since this improved process doesnot use 2-(2-hydroxyethoxy)ethyl-1-piperazine. It also obviates the needto use carboxyethyl piperazine which is used to prepare2-(2-hydroxyethoxy)ethyl-1-piperazine.

[0006] Many Pharmaceuticals are developed as salts of pharmacologicallyacceptable acids or bases. This is usually done if the biologicallyactive substance itself has a physical form which makes it unsuitable tohandle in manufacturing processes. Most manufacturing processes involvematerials handling in mixing and formulation which is facilitated by theactive materials being either a liquid or free-flowing high meltingsolids. Although salts can be made with suitable acids or bases theseoften add nothing to the therapeutic benefit of the pharmaceutical andare therefore redundant biologically. It would be better if thepharmaceutical could be manufactured as the pure active substance.

[0007] The reported synthesis of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineprovides11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineas a fumarate salt since it has been necessary to prepare the salt toefficiently obtain a sufficiently pure product. Moreover. to prepare thefumarate salt it has been necessary to first prepare the hydrogenfumarate salt and subsequently convert it to the fumarate.

[0008] The present invention is based. at least in part. on an improvedmethod of purifying the compound of formula I. and in particular on amethod of purifying the compound of formula I such that the compound offormula I is obtained in a crystalline form.

[0009] According to the present invention there is provided crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine.

[0010] The crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinemay be converted into one of its pharmaceutically acceptable salts andso the present invention also provides crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][4,1]thiazepineor a pharmaceutically acceptable salt prepared therefrom.

[0011] The crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineis generally provided in a substantially pure form. It is generallypreferred that the crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineis greater than 90% pure. more preferably 99% or greater than 99% pure.

[0012] According to the present invention there is also provided aprocess for preparing crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineor a pharmaceutically acceptable salt thereof which comprisescrystallising11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinefrom a non-aromatic solvent; and whereafter, when a pharmaceuticallyacceptable salt is required, reacting11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewith an acid which affords a pharmaceutically acceptable anion.

[0013] According to the present invention there is also provided aprocess for preparing crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineor a pharmaceutically acceptable salt thereof which comprisescrystallising11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinefrom a non-aromatic solvent substantially in the absence of water;

[0014] and whereafter, when a pharmaceutically acceptable salt isrequired, reacting11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewith an acid which affords a pharmaceutically acceptable anion.

[0015] The crystallisation may be initiated with the aid of a seedcrystal.

[0016] The salts of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewill generally comprise acid-addition salts. Convenient salts may beselected from those pharmaceutically acceptable salts known in the art.These may be obtained by any conventional salt preparation method knownin the art. For example. salts may be obtained by reacting11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewith a convenient acid. such as. hydrochloric acid. maleic acid. fumaricacid, citric acid, phosphonic acid. methanesulphonic acid and sulphuricacid.

[0017] Preferred salts include fumarate salts and in particular thehemi-fumarate salt. It is generally preferred that the fumerate salt of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineisbis-[11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine]fumarate.

[0018] It is generally preferred, for example, that the solvent is dry.It is further preferred that the11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineis also dry so that the solution formed on dissolving11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinein the solvent is substantially free from water. More especially. thesolution formed in the crystallisation process should be free fromwater.

[0019] Thus, in a preferred embodiment there is provided a process forpreparing11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine,or a pharmaceutically-acceptable salt thereof, which comprisescrystallising11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinefrom a solution of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine in a non-aromatic solvent which is free from water. Thecrystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinemay, if desired, be converted to a pharmaceutically-acceptable salt, asmentioned above.

[0020] Examples of suitable solvents include, for example esters such asthose of formula R¹CO₂R² wherein R¹ and R² are alkyl groups; ethers offormula R³OR⁴ wherenin R³ and R⁴ are alkyl groups; and ketones offormula R⁵COR⁶ wherein R⁵ and R⁶ are alkyl groups.

[0021] Particular values of R¹, R², R³, R⁴, R⁵ and R⁶ include, forexample, (1-6C)alkyl such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl.Conveniently, R¹, R², R³ and R⁴ are selected from (1-4C)alkyl.

[0022] Specific examples of suitable solvents include, for example,ethyl acetate. isobutyl acetate, methyl iso-butylketone and methyltert-butyl ether.

[0023] Solvents of particular interest include. for example. ethers.Thus. a solvent of particular interest is methyl tert-butyl ether.

[0024] The temperature ofthe solution containing11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinemay be decreased during the crystallisation. In general, the temperaturewill be decreased to about O C. Conveniently, the temperature isdecreased gradually over a period of time. Thus, in a specific example.the temperature is decreased to ambient temperature (about 25° C.) andthen further decreased to about O C over a period greater than 1 hourand generally greater than 2 hours. In particular. the temperature isdecreased from ambient temperature to 0° C. over a period of about 2 to4 hours, preferably about 3 hours. Where a seed crystal is used it willgenerally be added to the crystallisation mixture when that mixture isat ambient temperature. In the case where the temperature is decreased,the seed crystal will, in general, be added just before the temperatureis decreased (from ambient temperature).

[0025] The quantity of solvent employed to crystallise11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewill vary according to the precise solvent selected. In particular thequantity of solvent is that which. when11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineis dissolved in it. gives a concentration (before crystallisation) ofabout 120 to 160 mg/ml, more particularly 130 to 150 mg/ml. It isgenerally preferred that the quantity of solvent is that which gives aconcentration (before crystallisation) of about 135 to 145 mg/ml.

[0026] In a particular embodiment of the present invention there isprovided a method of purifying11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinecomprising crystallising11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinefrom methyl tert-butylether in the absence of water.

[0027] Preferred, particular and specific conditions include thosementioned above.

[0028] As mentioned above, the crystalline product may, if desired, beconverted to a pharmaceutically acceptable salt.

[0029] In a further embodiment of the present invention there isprovided a method of preparing the fumarate salt of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine,which method comprises reacting crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewith fumaric acid.

[0030] The crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewill generally be prepared as herein before defined.

[0031] Crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewill generally be reacted with the fumaric acid in a solvent such as analcohol. Examples of suitable alcohols will include methanol andethanol. A particularly suitable solvent is ethanol which mayconvenienetly be in the form of industrial methylated spirits (IMS).

[0032] The present invention also provides a method of preparingcrystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine.or a pharmaceutically acceptable salt thereof. from a solution of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinein an aromatic solvent which process comprises:

[0033] a) adding water and an acid to the solution of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinein the aromatic solvent;

[0034] b) separating the aqueous and organic phases;

[0035] c) adding a non-aromatic solvent and a base to the aqueous phase;

[0036] d) separating the aqueous and the non-aromatic solvent phases;

[0037] e) drying the non-aromatic solvent phase;

[0038] f) crystallising11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinefrom the non-aromatic solvent; and whereafter, if a pharmaceuticallyacceptable salt is desired. reacting the11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewith an acid which affords a pharmaceutically acceptable anion.

[0039] Particular, preferred and specific values include the valuesmentioned above.

[0040] The aromatic solvent is preferably toluene.

[0041] It will be appreciated that the amount/strength of acid added instep (a) will be such that the aqueous phase is made acidic and theamount/strength of base added in step ((c) will be such that the aqueousphase is made basic.

[0042] The compound of this invention is a central nervous systemdepressant and may be used as a tranquilizer for the relief ofhyperactivity states. for example, in mice, cats, rats, dogs and othermammalian species, and additionally for the management of psychoticstates in man, in the same manner as chlorpromazine. For this purposethe11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine.or physiologically acceptable acid addition salt thereof, may beadministered orally or parenterally in a conventional dosage form suchas tablets, pill, capsule. injectable or the like. The dosage in mg/kgof body weight of a compound of the present invention in mammals willvary according to the size of the animal and particularly with respectto the brain/body weight ratio. In general. a higher mg/kg dosage for asmall animal such as a dog will have the same effect as a lower mg/kgdosage in an adult human. A minimum effcctive dosage for the compound offormula I will be at least about 1.0 mg/kg of body weight per day formammals with a maximum dosage for a small mammal such as a dog. of about200 mg/kg per day. For humans, a dosage of about 1.0 to 40 mg/kg per daywill be effective. for example. about 50 to 2000 mg/day for an averageperson weighing 50 kg. The dosage can be given once daily or in divideddoses, for example, 2 to 4 doses daily. The dose may be conventionallyformulated in an oral or parenteral dosage form by compounding about 25to 500 mg per unit of dosage of conventional vehicle, excipient, binder,preservative. stabilizer. flavor or the like as called for by acceptedpharmaceutical practice, for example, as described in U.S. Pat. No.3,755,340. The compound of formula I (or salt) may be used inpharmaceutical compositions as previously described or be contained inor co-administered with one or more known drugs.

[0043] Thus. according to the present invention there is also provided apharmaceutical composition comprising crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine,or a pharmaceutically acceptable salt prepared therefrom, together witha pharmaceutically acceptable diluent or carrier.

[0044] In particular, there is provided a pharmaceutical compositioncomprising crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineand a pharmaceutically acceptable diluent or carrier.

[0045] The present invention also provides a method of treatingneuropsychiatic disorders (in particular, a method of treatingpsychoses, more particularly schizophrenia) using crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine,or a pharmaceutically acceptable salt prepared therefrom.

[0046] In particular, the present invention provides a method oftreating neuropsychiatic disorders, comprising administering aneffective amount of crystallinel11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineto a warm-blooded mammal such as man. In particular, the presentinvention provides a method of treating psychoses, more particularlyschizophrenia.

[0047] The present invention also provides the use of crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinein the manufacture of a medicament for treating neuropsychiatricdisorders and in particular psychoses such as schizophrenia.

[0048] As mentioned above, the present invention offers advantages overknown methods of preparing11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineand its salts.

[0049] Firstly, the present invention provides crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine.In particular the invention provides proceses for the preparationcrystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewhich is of high purity. In general, the crystalline material had a highmelting point consistent with a crystalline solid of high purity andgood quality.

[0050] Previously, pure11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinehas been obtained by provision of a purified salt, the fumarate. Thishas necessitated preparation of the hydrogen fumarate salt followed bysubsequent conversion to the fumarate salt. This conversion is arelatively low output process which requires the use of relativelydilute reaction mixtures to ensure the formation of the desired fumaratesalt rather than a mixture of hydrogen fumarate and fumarate salt forms.

[0051] By utilising purified crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine, the fumarate salt may be prepared in a relatively highoutput process since the difficulties associated with obtaining thecorrect salt form are minimised.

[0052] The present invention also provides processes for the preparationof11-(4-[2-(2-hydroxyehtoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineand its salts in a more productive manner than previously reported whichuses plant and/or materials such as solvents more efficiently.

[0053] The invention will now be illustrated by the followingnon-limiting examples in which, unless stated otherwise:

[0054] (i) temperature are given in degrees Celsius (C): operations werecarried out at room or ambient temperature, that is. at a temperature inthe range of 18-25C.

[0055] (ii) evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals; 4.5-30 mmHg) with abath temperature of up to 60 C;

[0056] (iii) in general. the course of reactions was followed by TLCand/or HPLC and reaction times are given for illustration only;

[0057] (iv) melting points are uncorrected and (dec) indicatesdecomposition; the melting points given are those obtained for thematerials prepared as described: polymorphism may result in isolation ofmaterials with different melting points in some preparations;

[0058] (v) all final products were essentially pure by TLC and/or HPLCand had satisfactory nuclear magnetic resonance (NMR) spectra andmicroanalytical data.

[0059] (vi) yields are given for illustration only;

[0060] (vii) reduced pressures are given as absolute pressures inpascals (Pa); other pressures are given as gauge pressures in bars;

[0061] (viii) chemical symbols have their usual meanings; the followingabbreviations have also been used: v(volume), w(weight), mp (meltingpoint), L (liters), ml (milliliters), g (grams), mmol (millimoles), mg(milligrams), min (minutes). h (hours), IMS(industrial methylatedspirits); and

[0062] The11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewas prepared as described in granted European Patent No. EP 282,236.This compound may also be prepared as described in granted EuropeanPatent No.240,228.

EXAMPLE 1

[0063] (a) Water (106 ml) was added to a stirred mixture of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine(59 g) in toluene at 40° C. Concentrated hydrochloric acid (21.4 ml) wasadded to the mixture and the mixture was stirred vigorously for 15minutes at 40° C. The phases were separated.

[0064] Methyl tert-butyl ether (256 ml) was added to the aqueous phase.Aqueous sodium hydroxide solution (15.4 ml density 1.5 g/cm³) was addedand the mixture was warmed to 45° C. and stirred vigorously for 15minutes. The mixture was allowed to settle and the phases wereseparated. The organic phase was washed with water (2×25 ml) at 45° C.and then dried by distillation at 55 ° C. using a Dean and Starkseparator. The dried mixture was allowed to cool to 25° C. seeded andstirred overnight to give a solid. The mixture was cooled to 0 ° C. andmaintained at 0 ° C. for 4 hours. The solid was collected by filtration.washed with methyl tert-butyl ether and dried in a vacuum oven at 50 °C. overnight.

[0065] There was thus obtained11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine(46.7g) as a white crystalline solid. m.p. 82-84° C.

[0066] (b) IMS (35 ml) was added to free base (30.0 g) and the stirredmixture was heated at 60° C. in a 100 ml flask to give a solution. Thissolution was transferred to a 500 ml reactor vessel via a sinter. The100 ml flask was washed with warm (60 C.) IMS (10 ml) and the washingsadded to the reactor vessel. The mixture in the reactor vessel waswarmed to 60° C. with stirring.

[0067] Fumaric acid (4.65 g) and IMS (60 ml) were added to the 100 mlflask. The mixture was heated to 60° C. with stirring to give a solutionwhich contained a small number of solid lumps of material. The mixturewas added to the reaction vessel via the sinter so as to filter themixture and remove the lumps. The resulting mixture in the reactionvessel was stirred to give crystalline material.

[0068] IMS (10 ml) was added to the 100 ml flask, warmed to 60° C. andtransferred to the reaction vessel. The thick crystalline mass in thereaction vessel was heated to reflux and then allowed to cool to ambienttemperature, to give a solid. The stirred mixture was cooled to 0° C.and the temperature of the mixture maintained at this temperature for 1hour. The solid was collected by filtration and washed with cool (0 to5° C.) IMS (30 ml). This IMS had been used to wash the reaction vesselout. The solid was dried in a vacuum oven at 55° C. overnight to givebis-[11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine]fumarate as a white crystalline solid (32.7 g); 94.4% yield).

EXAMPLE 2

[0069] Using a similar method to that described in Example 1.11-(4-[2-(2-hydroxyethoxy)ethyl)-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewas crystallised from the solvents listed below in place of methyltert-butylether. Solvent Strength (%) Yield (%) M.P. (° C.) Ethylacetate^([1]) 100 39.7 —^([2]) Iso-butyl acetate 97.5 70.1 83-86 Methyliso-butylketone 99.4 69.7 83-86 Methyl iso-butylketone^([3]) 99.3 67.883-86 Methyl tert-butylether 100 86 83-86 Methyl tert-butylether 99 8183-86

[0070] Strength is a measure of purity. The % strength is the % ofdesired ingredient,11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine,in the weight of material isolated.

EXAMPLE 3

[0071] The following illustrate representative pharmaceutical dosageforms containing a compound of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineand salts thereof., for example as illustrated in any of the previousExamples, (hereafter referred to as “compound X”), for therapeutic orprophylactic use in humans: mg/tablet (a) Tablet Compound X 50.0Mannitol, USP 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Hydroxypropylmethylcellulose (HPMC), 2.25 Magnesium stearate 3.0 (b)Capsule Compound X 10.0 Mannitol, USP 488.5 Croscarmellose sodium 15.0Magnesium stearate 1.5

[0072] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art. The tablets may be enteric coatedby conventional means, for example to provide a coating of celluloseacetate phthalate.

1. A compound which is crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine.
 2. A compound as claimed inclaim 1 in which the crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineis greater than 90% pure.
 3. A compound as claimed in claim 2 whereinthe crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineis greater than 99% pure.
 4. A process for preparing crystalline11-(4-[2-(2-hydroxyethoxy)ethyl)-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine,or a pharmaceutically acceptable salt thereof which comprisescrystallising 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine from a non-aromatic solvent; andwhereafter. when a pharmaceutically acceptable salt is required,reacting11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewith an acid which affords a pharmaceutically acceptable anion.
 5. Aprocess for preparing1-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine,or a pharmaceutically-acceptable salt thereof, which comprisescrystallising 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine from a solution of1-(4-[2-(2-hydroxyethoxy)ethyl-1-piperazinyl)-debenzo[b,f][1,4]thiazepinein a non-aromatic solvent and in which the solution is substantiallyfree from water.
 6. A process as claimed in any one of claims 4 or 5wherein the non-aromatic solvent is selected from an ester of formulaR¹CO₂R² wherein R¹ and R² are alkyl groups; an ether of formula R³OR⁴wherein R³ and R⁴ are alkyl groups. and a ketone of formula R⁵COR⁶wherein R⁵ and R⁶ are alkyl groups.
 7. A process as claimed in claim 6wherein R¹, R², R³ and R⁴ are selected from (1-4C)alkyl.
 8. A process asclaimed in claim 6 wherein the non-aromatic solvent is selected fromethyl acetate, isobutyl acetate, methyl iso-butylketone and methyltert-butyl ether.
 9. A process as claimed in any one of claims 4 to 8wherein the solvent is selected from methyl tert-butyl ether.
 10. Aprocess of purifying11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinecomprising crystallising11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinefrom methyl tert-butylether in the absence of water.
 11. A process asclaimed in claim any one of claims 4 to 10 wherein the11-(4-[2-(2-hyddroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineand the non-aromatic solvent are heated to give a solution and thetemperature of the solution containing the11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineis decreased to ambient temperature and then further decreased to aboutO C over a period greater than 1 hour.
 12. A process as claimed in claim11 wherein the temperature is decreased from ambient temperature to 0°C. over a period of about 2 to 4 hours.
 13. A process as claimed inclaim 11 or 12 wherein the temperature is decreased from ambienttemperature to 0° C. over a period of about 3 hours.
 14. A process asclaimed in claim any one of claims 4 to 13 wherein the quantity of thenon-aromatic solvent is that which, when11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineis dissolved in it, gives a concentration (before crystallisation) ofabout 120 to 160 mg/ml.
 15. A process as claimed in claim 14 wherein thequantity of non-aromatic solvent gives a 135 to 145 mg/ml.
 16. A processas claimed in any one of claims 4 to 15 in which comprises reactingcrystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewith fumaric acid to give the fumarate salt of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine.17. A process for preparing crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine.or a pharmaceutically acceptable salt thereof, from a solution of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinein an aromatic solvent which process comprises: a) adding water and anacid to the solution of11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinein the aromatic solvent; b) separating the aqueous and organic phases:c) adding a non-aromatic solvent and a base to the aqueous phase; d)separating the aqueous and the non-aromatic solvent phases; e) dryingthe non-aromatic solvent phase: f) crystallising11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinefrom the non-aromatic solvent; and whereafter, if a pharmaceuticallyacceptable salt is desired. reacting the11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinewith an acid which affords a pharmaceutically acceptable anion.
 18. Aprocess as claimed in claim 17 wherein the aromatic solvent is toluene.19. A process as claimed in claim 17 or 18 wherein step (f) is carriedout as claimed in any one of claims 4 to
 17. 20. A pharmaceuticalcomposition comprising crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepineand a pharmaceutically acceptable diluent or carrier.
 21. The use ofcrystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinein the manufacture of a medicament for treating neuropsychiatricdisorders.
 22. The use of crystalline11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepinein the manufacture of a medicament for treating psychoses.